Drug-Induced Liver Injury Nizar A. Mukhtar, MD Swedish Organ Transplant & Liver Center 2017 Spring Hepatology Update April 29, 2017 1
DILI - Outline Definition/Epidemiology Pathogenesis Risk Factors Clinical Features/Diagnosis Management Common Consultations Prevention Future Directions 2 2
DILI - Clinical Significance More than 600 drugs and chemicals associated with DILI The leading cause of ALF in the U.S (50%) 30% of acute hepatitis cases; 10% of hepatology consults; 1% of admits Severe DILI is a life-threatening illness and mild-to-moderate DILI may reduce availability of effective therapies A leading cause of drug withdrawal from the marketplace and most common cause for FDA regulatory action Represents significant liability risk for physicians and marked financial losses for pharma industry 3 3
DILI Definitions and Categories Liver injury caused by drugs or other chemicals Mechanism of Hepatotoxicity Predictable/Intrinsic vs Unpredictable/idiosyncratic Pattern of Liver Injury Hepatocellular vs Cholestatic vs Mixed Clinical Trials ALT > 3x ULN vs Alk Phos > 2x ULN vs Tbili > 2x ULN + ALT or alk phos elev 4 4
DILI - Epidemiology Growing list of culprit drugs; majority idiosyncratic Incidence: 1 in 10,000 1 in 100,000 patients Incidence likely higher: detection limited by underreporting and diagnostic challenges French study*: 14 per 100,000 persons (8000 cases annually); 12% hospitalized; 6% died (~500 deaths annually) Antibiotics (45%) and herbal/dietary supplements (16%) most often implicated Hepatotoxicity more frequently recognized after drug enters market (e.g., troglitazone for DM) *Sgro et al. Hepatology 2002;36:451-5. 5 5
Hy s Law Derived from the observation of Hy Zimmerman that drug-induced hepatocellular jaundice is a serious clinical entity Aminotransferase elevation >3x ULN + bilirubin >2x ULN (+ alternative etiologies of liver disease excluded) Hepatocellular injury accompanied by jaundice implies impaired biliary excretion and globally impaired liver function Of 116 patients meeting these criteria, 76% required a liver transplant or died (10-50% mortality in subsequent studies) Term coined by Robert Temple who defined these criteria for use in clinical trials and FDA approval process Zimmerman, Hyman. Hepatotoxicity. 1999. 6 6
Drug Development FDA established reporting guidelines for pharmaceutical companies: ALT 3x ULN ALT 5x ULN Hy s Law ALF Hy Zimmerman 1916-1999 7 7
DILI - Pathogenesis Likely involves Multihit process Intracellular disruption, cell necrosis/lysis apoptosis, inhibition of bile transport, mitochondrial injury, immune response Adaptation Liver Injury At least six mechanisms of liver injury Lee WM. N Engl J Med. 2003;349:474-85. 8 8
DILI - Risk Factors Chalasani N and Bjornsson E. Gastroenterology. 2010;138:2246-2259. 9 9
Age Adults > children DILI Risk Factors Younger at risk for DILI from valproic acid, Reye syndrome DILI phenotype: hepatocellular younger cholestatic elderly Sex Women more susceptible? Women more likely to have: autoimmune DILI hepatocellular DILI severe DILI 10 Lucena et al. Hepatology. 2009;49:2001-2009. 10
DILI Risk Factors Dose Metabolism: Liver metabolism associated with more ALT >3xULN (34% vs 10%; P.007) Liver failure (28% vs 9%; P.001) Liver transplantation (9% vs 1%; P.045) Fatal DILI (23% vs 4%; P.0003) 11 Lammert et al. Hepatology. 2010;51:615-620. 11
DILI Risk Factors Drug Interactions: Enzyme induction reactive metabolites inhibition increased drug conc e.g., Rifampin causes increased INH hepatotoxicity Liver Injury Alcohol Consumption: Increased risk for DILI from methotrexate, isoniazid, halothane or acetaminophen No significant association with severity or chronicity of DILI 12 *Andrade et al. Hepatology. 2006;44:1581-1588. 12
A stubborn misconception regarding susceptibility to hepatic injury has been the view that patients with preexisting liver disease are more likely than others to experience hepatic injury on exposure to drugs that cause liver damage - Hyman Zimmerman DILI Risk Factors Underlying Disease States: Chronic liver disease patients are at higher risk for complicated courses and adverse outcomes from DILI Co-morbid illnesses such as HIV, HBV, HCV, diabetes, and fatty liver disease may increase risk, but evidence is weak Genetic factors: CYP isoenzymes polymorphisms HLA haplotypes; phase I and II enzyme variants Immune response Hepatobiliary transporters 13 13
DILI - Clinical Features Characterized by a broad range of clinical patterns mimics virtually any form of liver disease Often asymptomatic or associated with vague symptoms: fatigue, anorexia, nausea, RUQ discomfort, and dark urine Labs: liver injury (enzyme elevations) or impaired liver function (elevated Tbili, albuminemia, coagulopathy) DILI usually resolves with discontinuation of the drug without significant morbidity or long-term consequences Liver tests may improve over time despite continued use of the drug poorly understood process of adaptation Severe DILI can have serious consequences (Hy s Law) 14 Reuben A. Hepatology 2004;39(2):574-8. 14
DILI Diagnosis DILI is a diagnosis of exclusion that relies on clinical judgment Six important features to consider to make the diagnosis: Time to onset Time to recovery Clinical pattern: injury pattern and clinical phenotype Exclusion of other causes of liver injury Whether the drug is a known cause of liver injury Response to re-exposure 15 15
DILI Diagnosis Time to onset Time from first day of therapy to onset of liver injury Typically 5 days to 3 months Short incubation period hypersensitivity reactions (Ex: sulfonamide and macrolide antibiotics) Long incubation period 3 to 12 months (Ex: INH and flutamide), or after years (Ex: amiodarone, minocycline) May be difficult to define Time to recovery Time from stopping drug to full recovery from liver injury Typically few days to weeks Sometimes rapid (Ex: acetaminophen, niacin), or prolonged 16 16
DILI Clinical Phenotypes Subclinical Liver Enzyme Elevations Acute liver injury Acute hepatitis/necrosis Cholestatic injury Mixed pattern Acute steatosis Chronic hepatocellular injury Chronic hepatitis Chronic steatosis/ Steatohepatitis Fibrosis and Cirrhosis Chronic cholestatic injury Other Chronic intrahepatic cholestasis Vanishing bile duct syndrome Biliary sclerosis Vascular disease Granulomatous hepatitis Neoplasia 17 17
DILI Clinical Phenotypes Subclinical enzyme elevations Mild ALT or alk phos elevation without jaundice or Sx Spontaneous improvement within weeks Ex.: INH, HAART, MTX, ASA, acetaminophen Acute Liver Injury 18 *Navarro, V and Senior, J. N Engl J Med. 2006. 354;7:731-9. 18
* Acute hepatitis DILI Clinical Phenotypes Resembles acute viral hepatitis; marked ALT elevation Sx: prodromal period of fatigue, nausea, anorexia abdominal discomfort, dark urine and jaundice Liver bx: resembles viral hepatitis Ex: INH, ketoconazole, flutamide Acute hepatic necrosis Resembles acute ischemic or toxic injury Rapid onset of injury and rapid resolution Hepatic dysfunction occurs early, preceding jaundice Sx: nausea, vomiting, abd pain AMS, somnolence, coma Liver bx: centrolobular necrosis Ex: acetaminophen, ASA, amiodarone 19 19
DILI Clinical Phenotypes * Pure or bland cholestasis Cholestasis; Alk phos and GGT elevation Sx: Itching, jaundice, dark urine, but otherwise well Liver bx: intrahepatic cholestasis Ex: anabolic steroids, estrogen, azathioprine, mercaptopurine Cholestatic and mixed hepatitis Most common phenotype; elevated alk phos + ALT elev Arises 2 to 12 weeks after starting medication; can be mild and short lived or severe and prolonged Sx: fatigue, nausea, dark urine, itching, jaundice Liver bx: intrahepatic cholestasis, inflammation, necrosis Ex: amoxicillin/clavuanate, sulfonylureas, macrolide abx, phenytoin 20 20
Acute steatosis DILI Clinical Phenotypes Rare and often severe form of DILI Caused by inhibition of mitochondrial function and alterations of fat metabolism Division of Gastroenterology Sx: nonspecific prodromal sx acute liver failure (coagulopathy, hyperammonemia and lactic acidosis) Liver bx: microvesicular fat macrovesicular fat and liver cell injury Ex.: antiviral drugs, tetracycline, linezolid 21 21
DILI Clinical Phenotypes Chronic hepatitis Liver injury >6 months 5-10% of cases of DILI will not resolve within a few weeks to months May be due to slow resolution of severe acute injury vs triggering of chronic liver disease such as AIH or PBC Ex: INH, nitrofurantoin, statins, methyldopa Autoimmune hepatitis Hepatocellular injury pattern accompanied by presence of high titers of ANA, ASMA and IgG Long latency periods (months or years); symptoms and lab abnormalities resolve once medication is stopped Ex: methyldopa, nitrofurantoin, minocycline, hydralazine, fenofibrate 22 22
DILI Clinical Phenotypes Chronic steatosis/ Steatohepatitis Uncommon and often difficult to distinguish from spontaneous NAFLD Insidious onset without signs or symptoms of liver disease; arises months to years after initiation of therapy Mild AST/ALT elevations; imaging suggestive of steatosis Liver bx: steatosis +/- lobular inflammation and ballooning degeneration Ex: chemotherapeutic agents (5-fluorouracil, cisplatin, tamoxifen), griseofulvin, methotrexate Cirrhosis DILI is a rare cause of cirrhosis; likely due to unrecognized liver injury Ex: methyldopa, amiodarone, methotrexate, valproate 23 23
DILI Clinical Phenotypes Vanishing bile duct syndrome Acute cholestatic liver injury bile duct injury and ductopenia Transient or progresses to biliary cirrhosis, hepatic failure or death Ex: augmentin, NSAIDs, sulfonamides Sinusoidal obstruction syndrome (busulfan, phytotoxins) Endothelial cell injury venoocclusive disease Rare; can lead to ALF Ex: busulfan, phytotoxins Nodular regenerative hyperplasia Endothelial cell injury regenerative nodules; no fibrosis Can cause portal HTN and liver dysfunction Ex: azathioprine, oxaliplatin Liver tumors and cancer Chronic hepatic injury or growth stimulation adenoma, HCC Ex: estrogen, androgenic steroids 24 24
DILI Diagnosis Exclusion of Other Diagnoses Perform careful history: Risk factors for viral hepatitis Alcohol use Weight gain Hx of autoimmune disease Hx of cardiac failure, shock Hx of drug use, including Rx and non-rx drugs and herbals Labs/studies: Viral hepatitis workup AIH workup Imaging for evaluation of biliary system, to r/o vascular insult Assess for features of fatty liver disease 25 Navarro, V and Senior, J. N Engl J Med. 2006. 354;7:731-9. 25
Response to re-exposure DILI Diagnosis Reappearance of liver injury following re-exposure offers convincing evidence in support of DILI Re-challenge is usually not advisable; can lead to rapid recurrence of DILI or greater severity of injury Re-challenge may be warranted if medication is considered life-sustaining and initial injury was mild, rapidly reversed, and/or atypical for the agent Known association with DILI (google: NIH Livertox ) 26 26
Various causality instruments have been developed with the goal of enhancing the reliability of causality assessment One of the most popular is the Roussel-Uclaf Causality Assessment Method (RUCAM) numerical weighting of key features in 7 domains: temporal relationship (latency and recovery), risk factors, concomitant drug use, exclusion of other etiology, prior information about liver injury and the drug, and the response to re-challenge Now available as an online calculator that generates an overall numerical score intended to reflect the probability of causality The gold standard for diagnosis of DILI remains expert opinion Benichou C. J Hepatol. 1990;11(2):272-6. DILI Diagnosis 27 27
DILI - Management Mainstay of therapy is drug discontinuation Avoid re-exposure to the implicated drug Specific therapies available: NAC for acetaminophen L-carnitine for valproate Cholestyramine for leflunomide Ursodeoxycholic acid for cholestatic DILI Steroids for hypersensitivity reactions Patients with severe DILI should be referred to a liver transplant center (Remember Hy s Law ) Report cases of DILI to MedWatch 28 28
DILI Future Directions Holy Grail : developing robust and accurate tests to detect the specific genetic or environmental traits that increase risk for DILI Pharmacogenomics: identificiation of gene polymorphisms or RNA-expression profiles before a patient uses a drug 29 29
Thanks for your attention! 30
DILI Case 1 A 66 year old Hispanic man was in good health except for hypertension for which he had been taking enalapril for more than a decade. Because of a positive purified protein derivative (PPD) tuberculin skin test, he was started on a 6 month course of isoniazid [300 mg daily with pyridoxine]. Laboratory tests taken before starting therapy were normal. He remained asymptomatic until onset of nausea and indigestion during week 6 of therapy. He denied fever or rash. He had not taken any over-the-counter medications, herbals or acetaminophen. He had a history of heavy drinking but had stopped 4 years previously. Physical examination showed jaundice but no signs of chronic liver disease. Laboratory tests showed a total bilirubin of 6.3 mg/dl, ALT 2326, and alk phos 114. Tests for hepatitis A, B and C were negative. Serum ANA was strongly positive (1:20,480), but smooth muscle antibody was negative, and immunoglobulin levels were normal. Liver imaging showed no evidence of biliary obstruction. Isoniazid was stopped promptly and he began to improve within days. Enalapril was restarted but therapy for latent tuberculosis was not pursued. One month later, he was asymptomatic and liver tests had returned to baseline. 31 31
DILI Isoniazid Mainstay of TB therapy; inhibits mycobacterial cell wall synthesis One of the most common causes of serious, idiosyncratic liver injury in the United States; 14% of transplants for DILI Transient aminotransferase elevations in 10 to 20% Aminotransferase elevation > 5x ULN in 3-5% Causes two syndromes of hepatotoxicity: Mild INH hepatotoxicity and INH hepatitis Mild INH hepatotoxicity Mildly elevated aminotransferases (<100 IU/L) Liver bx: minor, focal hepatocellular damage Adults > children; men = women Excellent prognosis; overall mortality rate of 0.001% Management: INH can be continued with careful monitoring 32 32
INH Hepatitis: Less common, but more serious liver injury syndrome Features indistinguishable from viral hepatitis Cumulative rate in combination 0.6%; monotherapy 0.1-0.3% Risk increases with age: DILI Isoniazid 20 to 34 years 0.3 percent 35 to 49 years 1.2 percent 50 to 64 years 2.3 percent Over age 65 years 4.6 percent Additional risk factors: regular alcohol use, concurrent liver disease including viral hepatitis, cirrhosis, HIV, concurrent rifampin or pyrazinamide, female gender, AA or Asian race, genetic factors (slow acetylator status, cytochrome polymorphisms) Kopanoff et al. Am Rev Respir Dis. 1978; 117:991. 33 33
DILI Isoniazid INH Hepatitis: occurs within 2-3 months Sx: fatigue, malaise, anorexia, nausea, vomiting, flu-like sx, RUQ pain occur days to weeks prior to onset of jaundice Labs: elevated aminotransferases with variable elevations of alk phos, bilirubin, and INR; autoantibodies can also be detected May be self-limited, but may progress to severe liver failure with massive hepatocellular necrosis in up to 10% of cases Liver bx: ranges from focal to diffuse necrosis to multilobular, bridging fibrosis and massive necrosis Mechanism of hepatotoxicity: Accumulation of toxic intermediate of metabolism Rates of injury higher among slow acetylators of INH metabolites; CYP 2E1 abnormalities also implicated Rapid recurrence of injury with re-challenge suggests a component of immune-mediated injury *Kopanoff et al. Am Rev Respir Dis. 1978; 117:991. 34 34
DILI Management of INH Hepatitis Normal baseline liver function: discontinue INH if AST >5x ULN if asymptomatic and >3x ULN if symptomatic Abnormal baseline liver function (aminotransferases >3x ULN at baseline): discontinue if increased 2-3 x above baseline or if jaundice, AMS Rule-out viral hepatitis; screen for alcohol use, other hepatotoxins Weigh risk vs benefits: If AST decreases to <2x ULN, injury was mild, and INH considered essential, may reinitiate with lower dosing and close monitoring of LFTs (up to 80% of persons tolerate further treatment) Patients should receive detailed information about signs and symptoms of hepatitis and instructed to stop INH immediately upon onset of symptoms Baseline and monthly clinical and biochemical monitoring indicated for patients with preexisting liver disease or age >50 35 35
DILI Case 1 INH Hepatitis A 66 year old Hispanic man developed nausea followed by dark urine and jaundice 6 weeks after starting isoniazid for latent tuberculosis. Key Points: An acute viral hepatitis-like syndrome arising 6 weeks after starting therapy is typical of isoniazid hepatitis Symptoms and signs may worsen for a few days after stopping isoniazid, but then usually improve rapidly Pattern of injury is hepatocellular; ANA reactivity can be seen, but with absence of other features that would suggest autoimmune hepatitis Age > 35 years is the single major risk factor for isoniazid hepatitis and treatment of latent TB should be done with caution; alcohol use may also be a risk factor Patients should be informed of the risk of liver injury and warned of the signs and symptoms of liver injury Routine biochemical monitoring is prudent if there is pre-existing liver disease or perceived increased risk for liver injury. The mortality rate of isoniazid hepatitis with jaundice is at least 10% 36 36
DILI Case 2 A 51 year old man with active rheumatoid arthritis was treated with methotrexate at an initial dose of 7.5 mg weekly, increasing to 15 mg weekly with daily folic acid and low doses of prednisone (5 mg daily) for four years. He had significant improvement and continued on both drugs for a total of 3.5 years. During the first year of therapy, he had minor and transient serum ALT elevations, but none were more than 3 times the upper limit of normal (ULN). Recently, his platelet count began to fall, and it remained low despite a decrease in the dose of methotrexate to 5 mg weekly. An abdominal ultrasound showed mild hepatomegaly, splenomegaly with increased echogenicity of the liver suggestive of fatty infiltration. He denied alcohol use and any history or risk factors for liver disease. Tests for hepatitis A, B and C were negative as were routine autoantibody tests. Liver tests including serum aminotransferase levels, alkaline phosphatase, bilirubin and albumin were normal and prothrombin time was not increased. A percutaneous liver biopsy showed marked fibrosis, early cirrhosis, mild steatosis and nuclear variability without inflammation or obvious necrosis. 37 37
DILI Methotrexate * Antineoplastic and immunosuppressive agent widely used in the therapy of leukemia, lymphoma, solid tumors, psoriasis and rheumatoid arthritis Acts by inhibition of folate metabolism, blocking dihydrofolic acid reductase, thereby inhibiting synthesis of purines and pyrimidines and decreasing DNA and RNA synthesis When given in high, intravenous doses, methotrexate can cause acute elevations in serum enzymes, and long-term methotrexate therapy has been associated with frequent but mild elevations in serum liver enzymes, as well as development of chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension. High dose IV methotrexate serum ALT levels can rise to 10 to 20 times the upper limit of normal (ULN) within 12 to 48 hours, but levels then fall rapidly to normal with only rare instances of jaundice or symptoms of liver injury With long-term, low-to-moderate dose methotrexate therapy, elevations in serum ALT or AST values occur in 15 to 50% of patients but are usually mild and self-limiting 38 38
DILI Methotrexate Induces a variety of histologic changes including steatosis, stellate cell hypertrophy, anisonucleosis (nuclei of varying sizes), and hepatic fibrosis Mechanism of liver injury thought to be direct toxicity through inhibition of RNA and DNA synthesis in the liver resulting in cellular arrest 30% of patients develop mild-to-moderate histological abnormalities (fat, cellular unrest, mild inflammation, nuclear atypia) and 2-20% of patients develop some degree of hepatic fibrosis Hepatic fibrosis and cirrhosis typically arise in 2-10 years; often associated with other factors for fatty liver disease (alcohol use, obesity, diabetes), use of other potentially hepatotoxic agents Prior use of high doses and daily methotrexate dosing was associated with development of hepatic fibrosis and rates of cirrhosis of greater than 20% after 5 to 10 years of treatment; with more modern dose regimens with folate supplementation, fibrosis and clinically apparent liver disease are rare 39 39
DILI Methotrexate Elevations of AST into the abnormal range are predictive of abnormal or worsening histological grade on liver biopsy Minimal deterioration was noted on serial liver biopsies when the MTX dose was adjusted for abnormalities in serum AST and albumin Noninvasive markers of hepatic fibrosis, such as serial platelet counts, serum procollagen III aminoterminal peptide (PIIIP), serum bile acids, hepatic ultrasound, advanced imaging techniques and transient elastography may help detect fibrosis in patients on longterm methotrexate Low dose, long-term methotrexate therapy has also been implicated in rare instances of reactivation of hepatitis B; all patients must be screened with HBsAg before starting tx There does not appear to be cross-reactivity in hepatic side effects between methotrexate and other disease modifying antirheumatic drugs (DMARDs) such as leflunomide, hydroxychloroquine, azathioprine, etanercept, or infliximab 40 40
DILI Methotrexate Initiation of therapy: careful history (alcohol use, viral hepatitis risk factors, family hx of liver disease) and physical examination Baseline liver tests, viral hepatitis serology Liver biopsy for patients with a history of excessive alcohol consumption, persistently abnormal AST or ALT values, or chronic hepatitis B or C infection Patients must be counseled about strict avoidance of alcohol and this conversation is documented on the clinic chart Monitoring based on RA guidelines: Monitoring of liver tests every 4-8 weeks every 8-12 weeks after 3 months on stable dose every 12 weeks after 6 months Liver biopsy should be performed if 6 of 12 tests are abnormal in any year (or 5 of 9 if testing is performed at six-week instead of monthly intervals) 41 Saag et al. Arthritis Rheum 2008; 59:762. 41
DILI Methotrexate A 51 year old man with rheumatoid arthritis developed thrombocytopenia after 7.5 years of methotrexate therapy and was found to have cirrhosis. Key Points: Significant hepatic fibrosis and portal hypertension can arise during methotrexate therapy without accompanying symptoms or significant elevations in serum aminotransferase levels; typically arises after 2 to 10 years of therapy A possible non-invasive marker for the development of significant fibrosis in this case was the decrease in platelet count Risk factors for developing methotrexate-related fibrosis include excessive alcohol use, underlying viral hepatitis Noninvasive tests such as PIIIP, hepatic imaging or elastography may have been helpful for identification of fibrosis in this patient who does not meet criteria for surveillance liver biopsies When cirrhosis develops, it is often non-progressive in nature despite continuation of methotrexate; however, therapy should be discontinued if advanced fibrosis or cirrhosis are detected 42 42
DILI Case 3 A 28 year old woman with HIV/AIDS developed serum ALT elevation to 133 U/L five weeks after starting an antiretroviral regimen of ritonavir, stavudine and lamivudine. She did not drink alcohol and tests for hepatitis A, B and C were negative. Despite the ALT elevations, she was asymptomatic and the abnormalities rapidly resolved with stopping antiretroviral therapy. Five weeks after restarting this regimen, however, she developed abdominal pain, nausea and jaundice. She was found to have weight loss, an enlarged and tender liver, and ascites. Serum ALT was 327 U/L, bilirubin 18.0 mg/dl and prothrombin index was 22%. She developed lactic acidosis and encephalopathy. A liver biopsy showed microvesicular steatosis, cholestasis and fibrosis with minimal inflammation. The antiretroviral agents were stopped, and she improved slowly; liver tests being normal 8 weeks later. Lamivudine and stavudine without ritonavir were re-introduced and she remained without evidence of recurrence of liver injury over the next 9 months. 43 43
DILI HAART HAART has resulted in prolonged life expectancy for HIV patients, but an increase in mortality from liver disease has been reported ARV therapy associated with fatty liver, steatohepatitis, liver failure, nonspecific hepatitis, advanced fibrosis, ESLD and nodular regenerative hyperplasia Documentation of hepatotoxicity difficult owing to concomitant use of multiple hepatotoxic drugs and underyling risk factors for liver disease among patients with HIV, including viral hepatitis All antiretroviral agents can cause hepatotoxicity NRTIs: stavudine and didanosine NNRTIs: nevirapine, efavirenz PIs: ritonavir Time of onset usually months to years after initiation; 24-48 mo Fluctuating LFTs often noted and do not necessarily correlate with histopathologic findings Bader. Am J Gastroenterol. 2010;105:978-980. 44 44
DILI HAART NRTIs: Resemble naturally occurring nucleosides and act by competitively inhibiting viral polyperase and terminating DNA synthesis Stavudine and didanosine most likely to cause hepatotoxicity Cause dose-dependent hepatotoxicity; rarely idiosyncratic hepatotoxicity Mechanism: cause hepatic mitochondrial injury by blocking mitochondrial DNA synthesis lactic acidosis, microvesicular steatosis and hepatic synthetic failure Clinical manifestations: hepatocellular injury pattern with mild aminotransferase elevations; jaundice arises late 45 45
DILI HAART NNRTIs: Inhibit HIV polymerase Nevirapine most common cause of serious DILI among all antiretroviral agents Often see cholestatic features, but initially hepatocellular injury pattern Mechanism: immunoallergic; supported by increased rates among women and patients with higher CD4 T cell counts; production of toxic intermediates also implicated Clinical manifestations: usually transient ALT elevation; ALT elevation >5x ULN in 4-20%; symptomatic liver injury in 1-5% with potential to cause severe or fatal liver injury; abdominal pain, fatigue, fever, rash, jaundice often seen; can also present with features of immunoallergic hepatitis (rash, fever, eosinophilia) 46 46
DILI HAART PIs: Inhibit HIV-1 protease activity needed for viral replication Ritonavir most frequent cause of PI-related hepatotoxicity Risk of severe hepatotoxicity is 5-fold higher among patients taking ritonavir Time to onset 1 to 8 weeks; variable patterns of liver injury, ranging from hepatocellular to cholestatic Mechanism: unknown; metabolized by and inhibits CYP 3A4, which may lead to production of toxic intermediates; may cause flares of HCV or HBV in co-infected patients due to immune reconstitution Clinical manifestations: usually transient and asymptomatic ALT elevation when used at low booster doses; moderateto-severe elevations in aminotransferase levels >5x ULN in 15% treated with full doses; more common in HIV-HCV coinfection; rarely leads to clinically apparent ALI; re-challenge leads to recurrent liver injury Sulkowski et al. JAMA. 2000. 283;1:74-80. 47 47
DILI HAART Histopathologic findings include portal and lobular inflammation, micro- and macrosteatosis, NASH, mild-tosevere fibrosis, cirrhosis 5/6 patients with ARV-induced hepatoxicity had liver biopsy findings consistent with NASH (3 PI, 2 NRTIs, and 1 NNRTIs) 48 Akhtar et al. Eur J Gastroenterol Hepatol. 2008. 20(12):1194-204. 48
DILI HAART A 28 year old woman with HIV/AIDS developed symptomatic liver injury with HAART therapy including stavudine and ritonavir. Key Points: Hepatic failure, lactic acidosis and hepatic microvesicular steatosis are typical of the mitochondrial liver injury that occurs with the stavudine (NRTI) therapy Often difficult to attribute the injury to a specific agent and the pathogenesis of HAART-related hepatotoxicity may relate to drug-drug interactions among the antiretroviral agents Liver injury tends to regress when therapy is held; rechallenge with ritonavir is not recommended as it can lead to severe liver injury ALT levels often do not correlate with severity of liver injury, and a lower threshold for liver biopsy in HIV patients is warranted 49 49
DILI Case 4 A 47 year old man with familial hypercholesterolemia is referred to your office. He recently suffered a myocardial infarction, and his and his low-density lipoprotein (LDL) was 450 mg/dl (11.6 IU). The only therapy that lowered this patient s LDL below 200 mg/dl (5.18 IU) was statin treatment. Yet the cardiologist was adamant that the statin be stopped for fear of hepatotoxicity because the ALT was minimally out of range at 61 IU/l. 50 50
DILI Statins The most potent, best tolerated and most widely used cholesterol lowering agents Inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis decrease in total and LDL cholesterol Among most commonly prescribed drug in developed countries: 10-20% of adults Statins prevent about 33% of major cardiovascular events when compared to placebo; NNT is 3 Cause ALT elevation in up 10% of patients without liver disease; >3x ULN in 1% of patients Are statins hepatotoxic? 6500 subjects randomized to lovastatin vs. placebo: no difference 19,000 subjects randomized to pravastatin vs placebo: no difference 20,000 subjects randomized to simvastatin vs. placebo: no hepatitis Among 10,000 subjects receiving rosuvastatin: no hepatitis Bader. Am J Gastroenterol. 2010;105:978-980. 51 51
DILI Statins Statins may confer benefit in certain liver diseases: NASH histological and liver test improvements HCV decreased ALT levels and increased SVR rates Despite a lack of supporting evidence, package inserts continue to contain warnings regarding the potential for hepatotoxicity Estimated to cost $3 billion a year, routine ALT monitoring is not recommended; 1-10% of patients taking statins may be denied ongoing benefit 52 Bader. Am J Gastroenterol. 2010;105:978-980. 52
DILI Statins Rare cases of statin-induced DILI have been reported; rate of 1/100,000 to 1/1,000,000; number needed to harm of 1 million Until recently, only 40 cases of statin-induced DILI were reported in the literature; recent Swedish study* reported an additional 73 cases occurring over a period of 22 years Of seven statins on the market, DILI is most often seen with atorvastatin and simvastatin (most commonly prescribed) Significant statin-induced DILI is idiosyncratic, often occurs within 3-4 months and can be associated with hepatocellular (simvastatin) > cholestatic (atorvastatin) > or mixed injury pattern Mechanism of hepatotoxicity is unknown; mild self-limited ALT elevations likely due to toxic intermediate of drug metabolism; severe injury may be immune-mediated or due to failure of adaptation 53 53
DILI Statins Outcome Liver injury is usually self-limited and recovery is complete within 1 to 4 months Some reports of triggering autoimmune chronic hepatitis Rare instances of acute liver failure (0.2 cases per million); difficult to distinguish from idiopathic ALF Management mild ALT elevations are self-limited and do not require dose modification Should be discontinued if ALT > 10xULN or persists > 5xULN Universal monitoring of ALT not recommended; measure liver tests in patients with newly developed symptoms (nausea, lethargy, abdominal pain) Recurrence of injury with rechallenge has been reported and should be avoided Switching to another statin appears safe, but monitoring required 54 54
DILI Statins A 47 year old man with CAD s/p MI referred for evaluation of ALT 2x ULN in the setting of statin use. Key Points: Statins frequently cause mild ALT elevations, but this does not necessarily indicate significant liver injury Rare idiosyncratic DILI due to statins has been reported and can present with a hepatocellular > cholestatic > mixed injury pattern Routine ALT measurement is not indicated; patients who are symptomatic should undergo liver testing Statins should be held in patients with ALT >10x ULN or persistent elevations >5x ULN Re-challenge is not recommended There is no clear evidence of a class effect; a switch to an alternative statin may be attempted with close monitoring 55 * 55
Patient Education DILI Prevention Warn patients about sx of severe liver injury and instruct to discontinue and contact their MD/provider Counsel regarding interaction with drugs and alcohol Counsel to avoid re-exposure; document in chart Liver Test Screening Periodic screening recommended for many drugs Unclear benefit; marked elevations cannot be overlooked Legislation Restriction or elimination of potentially toxic drugs from the marketplace e.g., use of combined acetaminophen-opiate drugs and acetaminophen-containing cold/flu medications 56 56